Notch signaling regulates cell fate and morphogenesis in the zebrafish lateral line system Sensory nerves of the lateral line ganglion innervate the sensory hair cells in the neuromasts. Together they form a part of a sensory system on the surface of fish that detects water flow. The neuromasts are archetypical sense organs whose development and morphogenesis has remarkable similarities to diverse sensory organs like ommatidia in the Drosophila eye and hair cells of the mammalian ear. The posterior lateral line primordium (pLLp) is a cohesive collection of about a hundred cells. It migrates caudally under the skin in the zebrafish trunk and tail periodically depositing neuromasts from it trailing end. The migrating pLLp contains 3-4 proneuromasts at various stages of maturation. As they mature a sensory hair cell is specified at the center of the proneuromast. Support cells, which also serve as pool of progenitors, surround the hair cell. As they mature the proneuromasts form center-oriented epithelial rosettes. Eventually, mature proneuromasts are deposited from the trailing end of the migrating pLLp and sensory nerves of the lateral line ganglion innervate the sensory hair cells. The surrounding progenitor cells in the neuromast contribute to formation of additional sensory hair cells as the neuromasts mature. Understanding how a) new proneuromasts are initiated at the leading end of the pLLp, b) how sensory hair cells are specified at the center of these cells clusters, c) how they form center-oriented epithelial rosettes, d) how they are deposited from the trailing end of the migrating pLLp and, e) what regulates caudal migration of the pLLp, in the very accessible lateral line system of zebrafish embryos, provides an attractive context to understand the broader mechanisms regulating organogenesis in the developing embryo. It is proving to be an especially attractive system for understanding how the function of distinct signaling pathways is integrated and how specification of cell fate and morphogenesis within a developing organ is coordinated. Previous studies showed that as stable proneuromasts are deposited from its trailing end, formation of new proneuromasts is initiated by Wnt-dependent FGF signaling center at the leading end of the migrating pLLp. This FGF signaling center initiates atoh1a expression and Notch-mediated lateral inhibition restricts atoh1 expression to a central cell within maturing proneuromasts. We have now shown that the central atoh1a plays a critical role in regulating FGF signaling within maturing neuromasts at the trailing end of the migrating pLLp. Atoh1a expression drives expression of FGF ligands like FGF10, while inhibiting expression of its receptor FGFR1. Normally, the Notch-signaling dependent restriction of atoh1a expression allows the self-organization of a restricted FGF signaling center within maturing neuromasts as the central FGF expressing cell activates FGF signaling in its neighbors that express FGFR1. However, when Notch signaling fails, too many cells express atoh1a. They begin to express FGF and shut off expression of its receptor, FGFR1. This eventually leads to failure of FGF signaling, unregulated Wnt signaling and disorganization of the migrating pLLp. We have developed computer models to visualize how interactions between the FGF, Wnt and Notch signaling systems regulate the self-organization of the lateral line system. Computational modeling illustrates how interaction between the FGF, Wnt and Notch signaling systems and differential regulation of chemokine receptors could regulate cell fate, morphogenesis and migration of the pLLp. The modeling predicts a key role played by negative feedback in the self-organization of the lateral line system. We are carrying out experiments to tests predictions of the computer models.